Passivated nanoparticles

ABSTRACT

Passivated semiconductor nanoparticles and methods for the fabrication and use of passivated semiconductor nanoparticles is provided herein.

This application claims benefit of priority to U.S. Provisional Patentapplication No. 61/244,909 filed Sep. 23, 2009, which is herebyincorporated by reference.

FIELD

The invention relates to the field of semiconductor nanocrystals andmethods of making and using them. More particularly, the inventionrelates to passivated semiconductor nanocrystals and methods of makingand using them.

BACKGROUND

Semiconductor nanocrystals, also called quantum dots, are a unique typeof nanoparticle, which exhibit size-dependent properties that are notobserved in either their discrete atom or bulk phase counterparts. Theseproperties include, for example, narrow, tunable emission spectra,enhanced magnetic properties, altered electrical or optical activity,altered chemical or biological activity, and extended fluorescencelifetimes and enhanced emission and photostability relative totraditional organic fluorophores. Semiconductor nanocrystals arecurrently under investigation for applications in fundamental scientificresearch efforts to potential applications in the optoelectronics,high-density memory, lasing media, solar cell, and biolabelingindustries, among others.

Semiconductor nanocrystals of the prior art, while exhibiting remarkableand commercially relevant properties, are vulnerable to a number ofdegradation processes, such as for example, oxidation, hydration, orphoto-ionization. Among these, are processes that directly attack theinterior of the nanoparticles such as oxidation, and processes thatattack or modify the surfaces of the nanoparticles. Interior-attackprocesses over time may irreparably modify the constituent materials andthereby eliminate their functionality altogether. Surface-attack andsurface-modification processes result from interactions of the surfacesof the nanoparticles with surrounding media. For example, temperature,electrolyte concentration, and pH in surrounding aqueous media maycontribute to nanocrystal degradation.

SUMMARY

Various embodiments of the invention are directed to a method forfabricating a passivated semiconductor nanocrystal, said methodcomprising the steps of: coating the surface of an alloy-gradientnanoparticle with an aluminum layer; and oxidizing the surface of saidaluminum layer to form an aluminum oxide layer. In some embodiments, theoxidizing step includes exposing the aluminum layer to an ambientenvironment. In other embodiments, the oxidizing step includes exposingthe aluminum layer to a controlled environment.

Certain embodiments of the invention are directed to a passivatedsemiconductor nanocrystal, prepared by a process comprising the stepsof: synthesizing an alloy-gradient nanoparticle, said nanoparticlecomprising at least one Group II element and two or more different GroupVI elements; applying a binary semiconductor coating over saidalloy-gradient nanoparticle, said coating having a wider band gap thanthe alloy-gradient nanoparticle; coating the surface of the binarysemiconductor coated alloy-gradient nanoparticle with an aluminum layer;and oxidizing the surface of said aluminum layer by exposure to anambient environment to form an aluminum oxide layer thereon, whereby asemiconductor nanocrystal of improved passivity is obtained. In someembodiments of the invention the alloy-gradient nanoparticle ishomogenous and in others, the alloy-gradient nanoparticle isnonhomogeneous.

According to other embodiments of the invention, a passivatedsemiconductor nanocrystal is prepared by: synthesizing an alloy-gradientnanoparticle, said nanoparticle comprising at least one Group II elementand two or more different Group VI elements; applying a binarysemiconductor coating over said alloy-gradient nanoparticle, saidcoating having a wider band gap than the alloy-gradient nanoparticle;coating the surface of the binary semiconductor coated alloy-gradientnanoparticle with an aluminum layer; and oxidizing the surface of saidaluminum layer by exposure to an ambient environment to form an aluminumoxide layer thereon, whereby a semiconductor nanocrystal of improvedpassivity is obtained. In certain embodiments, the synthesizing step maycomprise dissolving the at least one Group II element and the two ormore different Group VI elements in a solvent comprising octadecene anda fatty acid to provide a nanocrystal precursor solution and heatingsaid precursor solution.

According to other embodiments of the invention, a passivatedsemiconductor nanocrystal is prepared by: synthesizing an alloy-gradientnanoparticle, said nanoparticle comprising at least one Group II elementand two or more different Group VI elements; applying either a binarysemiconductor coating or an alloy-gradient coating comprising at leastone Group II element and two or more different Group VI elements oversaid alloy-gradient nanoparticle, said coating having a wider band gapthan the alloy-gradient nanoparticle; coating the surface of the coatedalloy-gradient nanoparticle with an aluminum layer; and oxidizing thesurface of said aluminum layer by exposure to an ambient environment toform an aluminum oxide layer thereon, whereby a semiconductornanocrystal of improved passivity is obtained. In certain embodiments,the synthesizing step may comprise dissolving the at least one Group IIelement and the two or more different Group VI elements in a solventcomprising octadecene and a fatty acid to provide a nanocrystalprecursor solution and heating said precursor solution. In someembodiments, the semiconductor coating is a binary semiconductorcoating. In some embodiments, the semiconductor coating is analloy-gradient coating comprising at least one Group II element and twoor more different Group VI elements.

In other embodiments of the invention, the method may further includethe step of coupling an active agent to the passivated semiconductornanocrystal. In some such embodiments, the active agent is associatedwith the surface of, encapsulated within, surrounded by, or dispersedthroughout the passivated semiconductor nanocrystal. In particularembodiments of the invention, the active agent may be coupled to thealuminum oxide layer. In still other embodiments, the method may furtherinclude the step of coupling a targeting moiety to the passivatedsemiconductor nanocrystal. In particular embodiments, the targetingmoiety may be coupled to the aluminum oxide layer. In other embodiments,the targeting moiety may be coupled to the active agent. In furtherembodiments of the invention, the method may include the step of coatingsaid passivated semiconductor nanocrystal with an additional passivationmaterial and in other embodiments, the method may include the step ofcoating said passivated semiconductor nanocrystal with a protectivecoating.

Other embodiments of the invention are directed to a method forpassivating a semiconductor nanocrystal, said method comprising thesteps of: applying a binary semiconductor coating over an alloy-gradientnanoparticle, said coating having a wider band gap than thealloy-gradient nanoparticle; coating the surface of the binarysemiconductor coated alloy-gradient nanoparticle with an aluminum layer;and oxidizing the surface of said aluminum layer by exposure to anambient environment to form an aluminum oxide layer thereon, whereby asemiconductor nanocrystal of improved passivity is obtained.

In certain embodiments of the invention, greater than 20% of thepassivated semiconductor nanocrystal surface area is functionalized withthe targeting moiety. In other embodiments, greater than 50% of thepassivated semiconductor nanocrystal surface area is functionalized withthe targeting moiety. In some embodiments, the passivated semiconductornanocrystal has surface properties effective for extended circulationunder physiological conditions.

Various embodiments of the invention are also directed to a method ofdiagnosing a disease in a subject, comprising administering to thesubject an effective amount of a pharmaceutical composition comprisingthe passivated semiconductor nanocrystals of the invention. Otherembodiments of the invention are directed to monitoring a biologicalprocess in vitro, said method comprising the steps of: dispensing thepassivated semiconductor nanocrystal to a sample, wherein the targetingmoiety specifically binds to a target in said sample and, wherein saidtarget is integral to a biological process; and imaging the sample or asection thereof in response to a stimulus, thereby monitoring thebiological process in vitro.

Other embodiments of the invention are directed to a method ofmonitoring a biological process in vivo, said method comprising thesteps of: administering the passivated semiconductor nanocrystal to asubject, wherein the targeting moiety specifically binds to a target inthe subject and, wherein said target is integral to a biologicalprocess; and imaging at least a portion of the subject, therebymonitoring the biological process in vivo.

BRIEF DESCRIPTION OF THE DRAWINGS

For a fuller understanding of the nature and advantages of the presentinvention, reference should be made to the following detaileddescription taken in connection with the accompanying figures, in which:

FIG. 1A is a log-scale excitation-normalized emission spectra ofunpassivated quantum dots disclosed in prior art;

FIG. 1B is a log-scale excitation-normalized emission spectra of thepassivated nanocrystals of one embodiment of the present invention;

FIGS. 2-5 illustrate the particle size distribution of passivatednanocrystals of some embodiments of the invention; and

FIG. 6 is a graph depicting the comparison of the fluorescence decay ofnon-passivated vs. passivated quantum dots.

DETAILED DESCRIPTION

This invention is not limited to the particular compositions ormethodologies described, as these may vary. In addition, the terminologyused in the description describes particular versions or embodimentsonly and is not intended to limit the scope of the invention. Unlessdefined otherwise, all technical and scientific terms used herein havethe same meanings as commonly understood by one of ordinary skill in theart. In case of conflict, the patent specification, includingdefinitions, will prevail.

As used herein, the singular forms “a”, “an” and “the” include pluralreference unless the context clearly dictates otherwise.

As used herein, the term “about” means plus or minus 10% of thenumerical value of the number with which it is being used. Therefore,about 50% means in the range of 40%-60%.

The terms “include”, “comprise” and “have” and their conjugates, as usedherein, mean “including but not necessarily limited to.”

As used herein, the terms “nanoparticles”, “nanocrystals”, and“passivated nanocrystals” refer to small structures in which theordinary properties of their constituent materials are altered by theirphysical dimensions due to quantum-mechanical effects, often referred toas “quantum confinement.” For the sake of clarity, the use of the term“nanoparticles” in this disclosure refers to objects possessingquantum-confinement properties, which are separated from one another inall three dimensions; enabling incorporation into liquids, vapors, orsolids.

“Optional” or “optionally” may be taken to mean that the subsequentlydescribed structure, event or circumstance may or may not occur, andthat the description includes instances where the event occurs andinstances where it does not.

In various embodiments of the invention, a passivation technique isprovided whereby nanoparticles may be passivated and incorporated into awide range of media without requiring the specialization or modificationof nanoparticle design and fabrication methods.

Embodiments of the invention are directed to passivated semiconductornanocrystals and methods of fabricating such passivated nanocrystals. Inthese embodiments, a passivation layer is formed on the outer layer ofthe nanoparticles. Passivation is a process in which a non-reactivelayer is created on the surface of the nanoparticles. Without wishing tobe bound by theory, the passivation layer may perform aquantum-mechanical function, including providing a tighter confinementof the quantum-mechanical wave functions, so that they do not extendbeyond the surface of the passivation material. Passivation furtherenables the nanoparticles to be used in a wide variety of media and in awide variety of applications.

Any passivation material known in the art may be utilized in the contextof the present invention. The key criteria for achieving passivation inthe context of this invention are the prevention of chemicalcontamination of the nanoparticle, the stability of the passivationmaterial in the intended application, and the quantum-mechanical bandgapof the passivation material of sufficient magnitude to prevent undesiredinteraction of the nanoparticle's desired wave functions with theambient chemical environment. For example, the passivation material mayinclude aluminum, carbon, and silicon, to name a few. Aluminum is apreferred passivation material because it is well-known to aggressivelyscavenge oxygen to form aluminum oxide (Al₂O₃), and Al₂O₃, once formed,is a strong barrier to oxidation and other degradation processes. Al₂O₃is also optically transparent and has a band gap for electrons and holesmuch greater than many of the semiconducting materials in the quantumdots themselves. In certain embodiments of the invention, one or morepassivation materials may be utilized in one or more layers.

Various embodiments of the invention are directed to a method forfabricating a passivated semiconductor nanocrystal, said methodcomprising the steps of: coating the surface of an alloy-gradientnanoparticle with an passivation material, such as, for example,aluminum; and oxidizing the surface of said passivation material to forman oxide layer. In some embodiments, the oxidizing step includesexposing the passivation material to an ambient environment. In otherembodiments, the oxidizing step includes exposing the passivationmaterial to a controlled or engineered environment. In some embodiments,the passivation material may be completely oxidized while in otherembodiments, the oxidation may be controlled so that only a fewmonolayers of the passivation material are oxidized.

The passivation techniques of the invention can be applied to a varietyof nanoparticles known in the art. The passivated nanoparticles ofembodiments of the invention may comprise, for example, core-shell,alloy or gradient structures of any material, such as a II-VI, IV-VI, ora III-V semiconductor material. In numerous embodiments, thenanoparticles comprise IV-VI or II-VI semiconductor nanoparticles, suchas CdS, ZnS, PbS, CdSe, ZnSe, PbSe, ZnTe, PbTe and CdTe nanoparticles.In other embodiments, ternary and quaternary semiconductornanoparticles, such as CdZnS, CdZnSe, CdSeS, CdZnTe, CdZnTeSe, andCdZnSSe, for example, may also be used. Some embodiments of theinvention are directed to a semiconductor nanocrystal comprising analloy or more than four elements. In addition, semiconductornanoparticles other than IV-VI or II-VI nanoparticles may also be used.These nanoparticles include, for example, GaAs, GaP, GaN, InP, InAs,GaAlAs, GaAlP, GaAlN, GaInN, GaAlAsP, GaAlInN, and various other III-Vmaterials.

Particular embodiments of the invention are directed to a passivatedsemiconductor nanocrystal comprising an alloyed-gradient nanocrystal.The term “alloyed”, as used herein, means that the semiconductormaterials comprising the quantum dot are capable of forming anamalgamated solid wherein the semiconductors are randomly distributedthroughout the solid. Furthermore, one of ordinary skill in the artrealizes that each of the at least two semiconductors of the alloyedsemiconductor quantum dots is a different semiconductor from theother(s). Likewise, one of ordinary skill in the art realizes that eachof the first semiconductor and second semiconductor of thealloyed-gradient quantum dot is different from the other.Alloyed-gradient quantum dots are generally more stable thanconventional core-shell quantum dots. In part, the composition-gradientavoids the stresses and defects associated with abrupt materialinterfaces with the beneficial effect of slowing or suppressing thepropagation of defects into the sensitive interior region of theparticles.

The alloyed-gradient semiconductor nanocrystals of some embodiments ofthe invention have a homogeneous composition. As used herein, the term“homogeneous composition” means that the nanocrystal has a uniformcomposition throughout, such that the composition is the same withrespect to the semiconductors comprising the nanocrystal and the molarratio of the semiconductors comprising the nanocrystal, i.e., thenanocrystal is uniform in composition from its centerpoint to itssurface. In other aspects, the alloyed-gradient semiconductornanocrystals do not have a homogeneous composition. For example, in someembodiments, the concentration of a first semiconductor graduallyincreases from the centerpoint of the nanocrystal to the surface of thenanocrystal, while the concentration of a second semiconductor graduallydecreases from the centerpoint of the nanocrystal to the surface of thenanocrystal.

In certain embodiments of the invention, the nanoparticles to bepassivated can have a semiconductor shell, i.e., can be encapsulatedwithin a shell comprising a semiconductor. The term “semiconductorshell”, as used herein, refers to a thin layer of semiconductor material(typically 1-10 atomic layers thick) deposited on the outer surface ofthe nanoparticle; this “semiconductor shell” is composed of a differentsemiconductor material than the nanoparticle itself. By “different” itis meant that either the ratio of the elements and/or the choice ofelements in the shell differs from that of the nanoparticle itself. Inaddition, the semiconductor shell should have a wider band gap than thenanoparticle core in order to efficiently protect the coreelectronically and sterically. The semiconductor shell can comprise anysemiconductor known in the art, including, but not limited to binarysemiconductor coatings, and coatings comprising at least one Group IIelement and two or more different Group VI elements. Some exemplarysemiconductor coatings include, but are not limited to, CdS, ZnS, PbS,CdSe, ZnSe, PbSe, ZnTe, PbTe, CdTe, CdZnS, CdZnSe, CdZnTe, CdZnTeSe,CdZnSSe, GaAs, GaP, GaN, InP, InAs, GaAlAs, GaAlP, GaAlN, GaInN,GaAlAsP, GaAlInN, among others. Preferably, the semiconductor shellcomprises ZnS, CdS, CdSe, CdTe, GaAs, or AlGaAs. Implementation of thiscore/shell structure, where a few monolayers of higher band gapsemiconductor materials are epitaxialy grown on prepared nanoparticles,or “cores”, have improved qualities regarding stability andphotoluminescence quantum efficiency. In particular, the overcoatingwith a wider bandgap semiconductor protects the surface nonradiativesites, thereby improving the luminescence efficiency of the nanocrystal.

Various embodiments of the invention are directed to the application ofaluminum coating onto alloy-gradient nanoparticles having asemiconductor shell and permitting such coating to reach full oxidationwherein the resultant Al₂O₃ passivation layer isolates the nanoparticlesagainst their environment, and provides robust quantum confinement. Insome embodiments, oxidation of the aluminum coating occurs at ambienttemperature. In other embodiments, oxidation of the aluminum coatingoccurs at elevated temperature, such as, for example, 100° C. In certainaspects of the invention, the Al₂O₃ passivation layer comprisesamorphous Al₂O₃

The fabrication methods for the passivated nanocrystals of the inventionmay be further modified in some embodiments to achieve desired features.For example, nanoparticle characteristics such as surface functionality,surface charge, particle size, zeta (ζ) potential, hydrophobicity, andthe like, may be optimized depending on the particular application ofthe passivated nanocrystals. For example, in some embodiments of theinvention, modified surface chemistry and small particle size maycontribute to reduced clearance of the nanoparticles. In otherembodiments, the passivated nanoparticles are stable in water or otherliquid medium without substantial agglomeration and substantialprecipitation for at least 30 days, preferably for at least 90 days, andmore preferably for at least 120 days. The term “stable” or “stabilized”means a solution or suspension in a fluid phase wherein solid components(i.e., nanoparticles) possess stability against aggregation andagglomeration sufficient to maintain the integrity of the compound andpreferably for a sufficient period of time to be useful for the purposesdetailed herein. As used herein, the term “agglomeration” refers to theformation of a cohesive mass consisting of particulate subunits heldtogether by relatively weak forces (for example, van der Waals orcapillary forces) that may break apart into particulate subunits uponprocessing, for example. The resulting structure is called an“agglomerate.”

The passivated nanocrystals of the invention can have any diameter, and,thus, be of any size, provided that quantum confinement is achieved. Incertain embodiments, the passivated nanocrystals described herein have aprimary particle size of less than about 10 nm in diameter. According toother embodiments, the passivated nanocrystals have a primary particlesize of between about 1 to about 500 nm in diameter. In otherembodiments, a primary particle size of between about 1 to about 100 nmin diameter, and in still other embodiments, a primary particle size ofbetween about 5 to about 15 nm in diameter. As used herein, the phrase“primary particle” refers to the smallest identifiable subdivision in aparticulate system. Primary particles can also be subunits ofaggregates.

The passivated nanocrystals of embodiments of the invention may beapplicable to a wide variety of applications. Without wishing to bebound by theory, the passivating layer may confine the wave function(s)to a large enough extent to enable the use of nanoparticle materialsotherwise considered as having too low a bandgap energy for applicationssuch as, for example, direct visible light generation from GaInAlPquaternary compounds. In another embodiment, the integration ofpassivating layer may also stabilize performance and managequantum-mechanical wave functions, for applicability in optoelectronic,photoluminescent, photovoltaic, magnetic, and electroluminescentapplications. As such, the passivated nanoparticles of embodiments ofthe invention may find application in polishing slurries, paints,coatings, inks, cleaning compositions, structural material, electronicdevices, light-emitting devices, light-receiving devices, codes, tags,data storage, optical switch, photodetector, transmission grating,optical filter, sensors, and lighting applications, among others.

In certain embodiments, the passivated nanocrystals may be used inoptoelectronic methods or as optoelectronic devices. For example, thepassivated nanocrystals may be used in light-emitting diodes (LEDs),solid-state lighting, or organic LEDs across the visible, ultravioletand infra red wavelengths. The passivated nanocrystals of the inventionmay also find application in solar cells. In some embodiments, thepassivated nanocrystals may be arranged and deposited onto a substrate,such as, for example, in an array as a thin film or layers of thin filmson a support substrate or as a coating on or around another electronicmaterial. The support substrate and layered passivated nanocrystal filmor other coated electronic material may be processed into bulksemiconductor materials having the unique properties of the passivatednanocrystals of the invention.

In addition, due to the superior photoemission and photostabilitycharacteristics, the passivated nanocrystals of the invention may beapplicable in in vitro and in vivo biological and medical applications,such as, for example, bioimaging, drug delivery, and gene therapy. Insuch embodiments, the passivated nanocrystals prepared according to themethods of the invention may be formed as a pharmaceutical composition.

Particular embodiments of the invention are directed to a method ofdiagnosing and/or treating a disease in a patient, comprisingadministering to the patient an effective amount of such pharmaceuticalcompositions containing the passivated nanocrystals. “Treatment” and“treating” refer to administration or application of a pharmaceuticalcomposition embodied in the invention to a subject or performance of aprocedure or modality on a subject for the purpose of obtaining atherapeutic benefit of a disease or health-related condition. A“disease” or “health-related condition”, as used herein, can be anypathological condition of a body part, an organ, or a system resultingfrom any cause, such as infection, genetic defect, and/or environmentalstress. The cause may or may not be known. The present invention may beused to diagnose, treat or prevent any disease or health-relatedcondition in a subject. Examples of such diseases may include, forexample, infectious diseases, inflammatory diseases, hyperproliferativediseases such as cancer, degenerative diseases, and so forth. In certainembodiments, the cancer may originate in the bladder, blood, bone, bonemarrow, brain, breast, colon, esophagus, duodenum, small intestine,large intestine, colon, rectum, anus, gum, head, kidney, liver, lung,nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue, oruterus. An “effective amount” or “therapeutically effective amount” of acomposition, as used herein, is a predetermined amount calculated toachieve a desired effect.

In certain embodiments, pharmaceutical compositions containing thepassivated nanocrystals may comprise more than one active ingredient,such as more than one type of passivated nanocrystal. The pharmaceuticalcomposition may alternatively comprise a passivated nanocrystal incombination with one or more active agents. The passivated nanocrystalmay be coupled to the active agent through any means, e.g., chemicalbonds, electrostatic interactions, cross-linkers, and the like. Inaddition, the active agent may be associated with the surface of,encapsulated within, surrounded by, or dispersed throughout thepassivated semiconductor nanocrystal. As used herein, the term “activeagent” means a compound utilized to image, impact, treat, combat,ameliorate, prevent or improve an unwanted condition or disease of apatient. The term “patient”, as used herein, refers to subjects to betreated including humans and other higher animals, and laboratorymodels, such as mice and rats. In another embodiment, one or more activeagents may be conjugated to one or more types of passivatednanocrystals.

In some embodiments of the invention, targeting moieties may be selectedto ensure that the passivated nanocrystals selectively attach to, orotherwise associate with, a selected marker or target. The term“target”, as used herein, refers to the material for which imaging,deactivation, rupture, disruption or destruction is desired. Throughfunctionalization of nanoparticle surfaces with such targeting moieties,the passivated nanocrystals are effective only at targeted sites, whichminimizes adverse side effects and improves efficacy.

In some embodiments of the invention, a linker may be utilized. The term“linker” as used herein, refers to any agent or molecule that bridgesthe passivated nanocrystals to the targeting moiety. This linker may beremoved from the nanoparticle by chemical means, by enzymatic means, orspontaneously. In some embodiments, the linker may be pharmacologicallyinert or may itself provide added beneficial pharmacological activity.The term “spacer” may also be used interchangeably as a synonym forlinker. Linkers used in the present disclosure may include, for example,lipids, polypeptides, oligonucleotides, polymers, and the like. It isalso within the scope of the invention that more than one linker may beused to attach a targeting moiety. For example, a first linker may beattached to a passivated nanocrystal followed by a second linker that isattached to the first linker A third linker may be attached to thesecond linker and so on and so forth. In addition, one linker may beattached to the passivated nanocrystal and one linker may be attached tothe targeting moiety. In this embodiment, the two linkers are joined toform the linker.

In various embodiments, the passivated nanoparticles may bewell-dispersed and unagglomerated, which may facilitate conjugation orfunctionalization of the passivated nanoparticle surfaces with targetingmoieties. As used herein, the terms “unagglomerated”, “nonaggregated”,and “unagglomeration” refer to a state of dispersion in a suspension. Inparticular aspects of the present invention, the passivated nanocrystalsmay be optimized with a specific ratio of conjugated to non-conjugatednanoparticle surface area, such that an effective amount of targetingmoiety is associated with the passivated nanocrystals. According to anembodiment of the invention, the portion of the surface area of thepassivated nanoparticle functionalized with a targeting moiety isgreater than 25% of the total surface area. According to anotherembodiment of the invention, the portion of the surface area of thepassivated nanoparticle functionalized with a targeting moiety isgreater than 50% of the total surface area. Increased density of thetargeting moiety will generally increase target binding. Alternatively,an increase in non-conjugated nanoparticle surface area may influenceinflammation, immunogenicity (i.e., the ability to provoke an immuneresponse), and/or nanoparticle circulation half-life. Furthermore, anincrease in non-conjugated nanoparticle surface area will typicallylower the rate of clearance of the nanoparticles from the circulatorysystem via the reticuloendothelial system (RES).

Exemplary targeting moieties include, for example, proteins, peptides,antibodies, antibody fragments, saccharides, carbohydrates, glycans,cytokines, chemokines, nucleotides, lectins, lipids, receptors,steroids, neurotransmitters and combinations thereof. The choice of amarker may vary depending on the selected target, but in general,markers that may be useful in embodiments of the invention include, butare not limited to, cell surface markers, a cancer antigen (CA), aglycoprotein antigen, a melanoma associated antigen (MAA), a proteolyticenzyme, an angiogenesis marker, a prostate membrane specific antigen(PMSA), a small cell lung carcinoma antigen (SCLCA), a hormone receptor,a tumor suppressor gene antigen, a cell cycle regulator antigen, aproliferation marker, and a human carcinoma antigen. In other aspects ofthe invention, targeting moieties are targeted to an antigen associatedwith a disease of a patient's immune system or a pathogen-bornecondition. In yet another aspect, targeting moieties are targeted tocells present in normal healthy conditions. Such targeting moieties maybe directly targeted to a molecule or other target or indirectlytargeted to a molecule or other target associated with a biologicalmolecular pathway related to a condition.

In another embodiment of the invention, the passivated nanocrystals canbe formulated into a depot. Depot formulations of passivatednanocrystals may include, for example, an implantable compositioncomprising the passivated nanocrystals and a porous material, whereinthe passivated nanocrystals are encapsulated by or diffused throughoutthe porous material. The passivated nanocrystal depot may be positionedin a desired location affiliated with the patient's body upon which thenanoparticles may be released from the implant at a predetermined rateby diffusing through the porous material.

Once the passivated nanocrystals have been prepared and optionallyfunctionalized, formulated or conjugated, they may be combined with anacceptable carrier to produce a pharmaceutical formulation, according toanother aspect of the invention. The carrier can be any suitable carrierknown in the art. Preferably, the carrier is a pharmaceuticallyacceptable carrier. With respect to pharmaceutical compositions, thecarrier can be any of those conventionally used and is limited only byfactors, such as, for example, chemico-physical considerations, such assolubility and lack of reactivity with the active compound (s) and routeof administration. It will be appreciated by one of skill in the artthat, in addition to the following described pharmaceuticalcompositions, the passivated nanocrystals may be formulated as inclusioncomplexes, such as cyclodextrin inclusion complexes, or liposomes.

The pharmaceutically acceptable carrier may be selected based on factorsincluding, but not limited to, the particular passivated nanocrystal andany active agent conjugated thereto, route of administration, locationof the target, and/or the time course of delivery. A variety of aqueouscarriers may be used, for example, (water, buffered water, isotonicsaline, dextrose and the like). For example, a concentrated sucrosesolution may be aseptically added to the sterile nanoparticle suspensionto produce a pharmaceutical formulation. The sucrose serves as acryoprotectant and a tonicity agent. Such a solution may be asepticallydiluted to the desired concentration.

The compositions of the invention can be administered by any suitableroute. Accordingly, there are a variety of suitable formulations of thepharmaceutical composition of the present inventive methods. Thefollowing formulations for oral, aerosol, parenteral, subcutaneous,intravenous, intramuscular, interperitoneal, rectal, and vaginaladministration are exemplary and are in no way limiting. One skilled inthe art will appreciate that these routes of administering thepassivated nanocrystals of the present invention are known, and,although more than one route can be used to administer a particularpassivated nanocrystal, a particular route of administration may providea more immediate and more effective response relative to another routeof administration.

Injectable formulations are among those pharmaceutical formulations thatare preferred in accordance with the present invention. The requirementsfor effective pharmaceutical carriers for injectable compositions arewell-known to those of ordinary skill in the art (see, e.g.,Pharmaceutics and Pharmacy Practice, J. B. Lippincott Company,Philadelphia, Pa., Banker and Chalmers, eds., pages 238-250 (1982), andASEP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630(1986), which is hereby incorporated by reference in its entirety).

Topical formulations are well-known to those of skill in the art. Suchformulations may be utilized in the context of embodiments of theinvention for application to the skin.

Formulations suitable for oral administration can consist of (a) liquidsolutions, such as an effective amount of the passivated nanocrystalsdispersed in a liquid carrier, such as, for example, water or saline;(b) capsules, sachets, tablets, lozenges, and troches, each containing apredetermined amount of active ingredient; (c) powders; (d) passivatednanocrystals suspended in a liquid carrier; and (e) emulsions. In someembodiments, liquid formulations may include diluents, such as water oralcohols, for example, ethanol, benzyl alcohol, and the polyethylenealcohols, either with or without the addition of a pharmaceuticallyacceptable surfactant. Capsule forms can be of the ordinary hard- orsoft-shelled gelatin type containing, for example, surfactants,lubricants, and inert fillers, such as lactose, sucrose, calciumphosphate, and corn starch. Tablet forms can include one or more oflactose, sucrose, mannitol, corn starch, potato starch, alginic acid,microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicondioxide, croscarmellose sodium, talc, magnesium stearate, calciumstearate, zinc stearate, stearic acid, colorants, diluents, bufferingagents, disintegrating agents, moistening agents, preservatives,flavoring agents, and pharmacologically compatible excipients. Lozengeforms can comprise the active ingredient in a flavored material, usuallysucrose and acacia or tragacanth, as well as pastilles comprising theactive ingredient in an inert base, such as gelatin and glycerin, orsucrose and acacia, emulsions, gels, and the like containing, inaddition to the active ingredient, such excipients as are known in theart.

The passivated nanocrystals prepared according to embodiments of theinvention, alone or in combination with other suitable components, canbe made into aerosol formulations to be administered via inhalation.These aerosol formulations can be placed into pressurized propellants,such as dichlorodifluoromethane, propane, nitrogen, and the like. Inother embodiments, the passivated nanocrystals may be formulated aspharmaceuticals for non-pressured preparations, such as in a nebulizeror an atomizer.

In other embodiments, the compositions of the present invention may beadministered parenterally. Typically, this will comprise the passivatednanocrystals dispersed or suspended in a pharmaceutically acceptablecarrier. The term “parenteral”, as used herein, means intravenous,intra-arterial, intramuscular, intra-peritoneal and to the extentfeasible, intra-abdominal and subcutaneous. Pharmaceutically acceptablecarriers suitable for parenteral administration include aqueous andnon-aqueous liquids, isotonic sterile injection solutions, which maycontain anti-oxidants, buffers, bacteriostats, and solutes that renderthe formulation isotonic with the blood of the intended recipient, andaqueous and non-aqueous sterile suspensions that may include suspendingagents, solubilizers, thickening agents, stabilizers, and preservatives.In certain embodiments, the passivated nanocrystals can be administeredparenterally in a physiologically acceptable diluent in apharmaceutically acceptable carrier, such as a sterile liquid or mixtureof liquids, including water, saline, aqueous dextrose and related sugarsolutions, an alcohol, such as ethanol, isopropanol, or hexadecylalcohol, glycols, such as propylene glycol or polyethylene glycol,dimethylsulfoxide, glycerol ketals, such as2,2-dimethyl-1,3-dioxolane-4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester orglyceride, or an acetylated fatty acid glyceride with or without theaddition of a pharmaceutically acceptable surfactant, such as a soap ora detergent, suspending agent, such as pectin, carbomers,methylcellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agents and other pharmaceuticaladjuvants.

Oils that may be used in parenteral formulations include, for example,petroleum, animal, vegetable, or synthetic oils. Specific examples ofoils include peanut, soybean, sesame, cottonseed, corn, olive,petrolatum, and mineral, to name a few. Suitable fatty acids for use inparenteral formulations include, for example, oleic acid, stearic acid,and isostearic acid. Ethyl oleate and isopropyl myristate arenon-limiting examples of suitable fatty acid esters.

Soaps for use in parenteral formulations of embodiments of the inventioninclude, for example, fatty alkali metal, ammonium, and triethanolaminesalts, and suitable detergents include cationic detergents such as, forexample, dimethyl dialkyl ammonium halides, and alkyl pyridiniumhalides, anionic detergents such as, for example, alkyl, aryl, andolefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, andsulfosuccinates, nonionic detergents such as, for example, fatty amineoxides, fatty acid alkanolamides, and polyoxyethylenepolypropylenecopolymers, amphoteric detergents such as, for example,allyl-b-aminopropionates, and 2-alkyl-imidazoline quaternary ammoniumsalts, and mixtures thereof.

In some embodiments, the parenteral formulations may containpreservatives and/or buffers. Additionally, in order to minimize oreliminate irritation at the site of injection, the parenteralcompositions of embodiments of the invention may contain one or morenonionic surfactants. For example, in some embodiments, a non-ionicsurfactant having a hydrophile-lipophile balance (HLB) of from about 12to about 17 may be included in the parenteral formulation. The quantityof surfactant in such formulation will typically range from about 5% toabout 15% by weight. Suitable surfactants may include, for example,polyethylene sorbitan fatty acid esters, such as sorbitan monooleate andthe high molecular weight adducts of ethylene oxide with a hydrophobicbase, formed by the condensation of propylene oxide with propyleneglycol. The parenteral formulations of certain embodiments may bepresented in unit-dose or multi-dose sealed containers, such as ampoulesand vials, and can be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid excipient, forexample, water, for injections, immediately prior to use.

Additionally, the passivated nanocrystals prepared according toembodiments of the invention, or compositions comprising such compounds,can be made into suppositories by mixing with a variety of bases, suchas emulsifying bases or water-soluble bases. Formulations suitable forvaginal administration can be presented as pessaries, tampons, creams,gels, pastes, foams, or spray formulas containing, in addition to theactive ingredient, such carriers as are known in the art to beappropriate.

In still other embodiments, the passivated nanocrystals may beadministered in the presence of an agent(s) or other suitablecomponent(s) that enhances efficacy, such as those that can furtherprotect the passivated nanocrystals and/or active agent(s) coupledthereto from degradation or those that can prevent rapid capture by thereticuloendothelial system (RES). One such component is poly(ethyleneglycol) (PEG) or PEG containing surfactants. Addition of PEG andPEG-containing copolymers to the surface of the passivated nanoparticlescan result in an increase in the blood circulation half-life of thenanoparticles by several orders of magnitude.

The amount of nanoparticles or pharmaceutical compositions administeredto a patient may vary and may depend on the body weight, age, and healthof the patient, the size and structure of the passivated nanocrystals tobe delivered, the disease being treated or imaged, and the location ofdiseased tissue. The term “diseased tissue”, as used herein, refers totissue or cells associated with solid tumor cancers of any type, such asbone, lung, vascular, neuronal, colon, ovarian, breast and prostatecancer. The term diseased tissue may also refer to tissue or cells ofthe immune system, such as tissue or cells effected by AIDS;pathogen-borne diseases, which can be bacterial, viral, parasitic, orfungal, examples of pathogen-borne diseases include HIV, tuberculosisand malaria; hormone-related diseases, such as obesity; vascular systemdiseases; central nervous system diseases, such as multiple sclerosis;and undesirable matter, such as adverse angiogenesis, restenosisamyloidosis, toxins, reaction-by-products associated with organtransplants, and other abnormal cell or tissue growth. Moreover, thedosage may vary depending on the mode of administration.

In order that the invention disclosed herein may be more efficientlyunderstood, the following examples are provided. These examples are forillustrative purposes only and are not to be construed as limiting theinvention in any manner.

Example 1 Passivated Alloy-Gradient Nanocrystal Preparation

Passivated CdZnSSe nanocrystals were fabricated as follows. To a 100 mlthree-neck round bottom flask, 0.16 mmol of CdO, 0.4 mmol of Zn(AC)2,200 μl of oleic acid and 8 ml of octadecene were added. The flask wasconnected to a vacuum and degassed for about 10 minutes, then filledwith high purity nitrogen, heated up to 300° C., and stirred until acolorless solution was formed. Stock solution of sulfur and seleniumwere prepared in a glovebox filled with 99.999% nitrogen. Seleniumpowder (1.00 g) was mixed with tributylphosphine (10.00 ml) and sulfurpowder (0.05 g) was mixed with octadecene (25.00 ml). An amount of theabove sulfur and selenium stock solutions were mixed together in a glassvial and diluted with octadecene up to 4 ml resulting in a solutionherein called an injection solution. The amount of sulfur and seleniumwas 1 mmol in total, the S to Se ratio was determined by the finalemission wavelength of the derived nanocrystals. The injection solutionwas removed from the glovebox using a syringe and injected into the Cdand Zn precursor solution quickly while the growth temperature wasraised to 270° C. This temperature was maintained for 40 to 60 minutesto allow the nanocrystals to grow to the desired size as determined bythe desired emission wavelength.

In the glovebox, a solution was prepared for use in the deposition ofone or more layers of ZnS onto the prepared nanocrystals. When no changein emission wavelength was observed of the above-prepared nanocrystals,the solution was injected slowly into the nanocrystal solution. Thisinjection process lasted approximately two minutes.

The resultant solution was added to a 50 ml conical centrifuge tube and5 ml hexanes and 15 ml of butanol were added. After sonication for about1 minute, 20 ml methanol was added. The nanocrystals were centrifugedand the supernatant was discarded. The nanocrystals were washed two moretimes with 10 ml of hexanes, precipitated with 20 ml of methanol andre-centrifuged. The purified nanocrystals were suspended in hexanes forfurther capping.

The purified nanocrystals were transferred to a three-neck round bottomflask and hexanes were removed by vacuum. Trioctylphosphine oxide (8.0g) and stearic acid (0.2 g) were added. The flask was vacuum purged for10 minutes and heated to 100° C. for 30 minutes and then to 200° C. for30 minutes. Capping material was prepared in a glovebox as follows: 40ul of dimethylzinc, 80 ul of hexamethyldisilathiane and 4 ml oftrioctylphosphine were mixed in a glass vial and sealed with a robberstopper. The capping solution was put in a syringe, removed from theglovebox, and slowly injected into the core solution over at least 10minutes. The resulting solution was stirred for 30 minutes at 200° C.,then removed from heat and allowed to cool to room temperature. Severalmonolayers of aluminum were then grown on the nanocrystals and thealuminum-coated nanocrystals were allowed to slowly oxidize at 100° C.for 2-3 hours.

Example 2 Passivated Alloy-Gradient Nanocrystal Preparation

As an example of the fabrication and performance of passivatednanoparticles of one embodiment of the invention, alloy-gradient CdSSequantum dots with ZnS shells were synthesized according to methodsdescribed in U.S. patent application Ser. No. 11/197,620, which isherein incorporated by reference in its entirety to the extent suchreference is not inconsistent with the explicit teachings of thisspecification. Several monolayers of aluminum were grown on thenanocrystals and the aluminum-coated nanocrystals were allowed to slowlyoxidize at 100° C. for 2-3 hours.

Example 3 Fluorescence Characterization

The Al₂O₃-coated alloy-gradient quantum dots were incorporated intopoly(methyl methacrylate) (PMMA) dissolved in toluene. The passivatedquantum dot composition was then spun onto a microscope slide in a thin(˜1 μm) layer and allowed to dry at room temperature. As a control,alloy-gradient quantum dots of the same design, but without an Al₂O₃outer coating were also fabricated and incorporated into PMMA dissolvedin toluene. Similarly, the unpassivated quantum dot composition was thenspun onto a microscope slide in a thin (˜1 μm) layer and allowed to dryat room temperature.

The microscope slides were placed on a custom slide holder andfluorescence spectra measurements were taken using a Shimadzu RF-5301Spectrofluorophotometer (Shimadzu Scientific Instruments, Columbia,Md.). The Shimadzu RF-5301 Spectrofluorophotometer was configured todetect both the Rayleigh-scattered excitation light to serve as areference and the quantum dot emission. The excitation wavelength wasset to 350 nm. The excitation normalized Shimadzu RF-5301Spectrofluorophotometer output values were then plotted as a function ofwavelength (nm).

FIG. 1A is a log-scale excitation-normalized emission spectra of theunpassivated alloy-gradient quantum dots, while FIG. 1B is a log-scaleexcitation-normalized emission spectra of the Al₂O₃-coatedalloy-gradient quantum dots. As shown in FIG. 1B, the Al₂O₃-coatedquantum dots exhibited no reduction in fluorescence and no shift inoutput wavelength. In comparison, as shown in FIG. 1A, the unpassivatedquantum dots suffered a four-fold reduction in fluorescence and a 10 nmblue shift. The blue shift and reduction of fluorescence are consistentwith oxidation of the unpassivated quantum dots and resultant loss ofefficiency.

Example 4 Accelerated Environmental Exposure Characterization

To test the assertion that the Al₂O₃ layer functioned to passivate thealloy-gradient core-shell quantum dots, a high-temperature,high-humidity test was designed. In this test, the microscope slidesfrom Example 2 were individually placed film-side-up on a stainlesssteel oven plate into a sealed 85° C. oven that contained a beaker ofdistilled water and was equilibrated to achieve approximately 100%relative humidity. Each microscope slide was exposed to this environmentfor 90 minutes. The microscope slides where then removed from the ovenand allowed to cool for 2-5 minutes.

The fluorescence characteristics of each sample were re-measured asdescribed in Example 2 to assess the impact of the high-temperature,high-humidity environment. As shown in FIG. 1A, the unpassivated quantumdots suffered a substantial reduction in fluorescence and a significant10 nm blue shift. Comparatively, as shown in FIG. 1B, the Al₂O₃-coatedquantum dots showed no reduction and no shift in emission wavelength andappear to be robust against high-temperature, high-humidity exposure.

Example 5 Particle Size and Zeta Potential Characterization

Passivated alloy-gradient nanoparticles were synthesized according tomethods provided in Example 1 and Example 2 and the passivatednanocrystals were functionalized with a variety of chemistries: SampleNC-540-O (Functional Group: —OH, Emission Peak (nominal): 570 nm,Emission Peak (actual): 570 nm); Sample NC-575-C (Functional Group:—COOH, Emission Peak (nominal): 575 nm, Emission Peak (actual): 575 nm);Sample NC-575-N (Functional Group: —NH₃, Emission Peak (nominal): 575nm, Emission Peak (actual): 575 nm); and Sample NC-665-C (FunctionalGroup: —COOH, Emission Peak (nominal): 665 nm, Emission Peak (actual):665 nm).

The zeta potentials of the passivated nanocrystal suspensions weremeasured by a Zeta PALS Analyzer based on the dynamic light scatteringprinciple (Brookhaven Instruments Co., NY). The pH was adjusted using0.1 M HNO₂ and 0.1 M KOH aqueous solutions. A Malvern Nanosizer (MalvernInstruments, UK) was used to determine the state of dispersion for thepassivated nanocrystal suspensions. The particle size distribution forSample NC-540-O (Functional Group: —OH) is shown in FIG. 2. Asillustrated in FIG. 2, the passivated nanoparticles have a primaryparticle size of 12.7 nm in diameter. FIG. 3 shows the particle sizedistribution for Sample NC-575-C (Functional Group: —COOH) and a primaryparticle size of 8.87 nm in diameter. FIG. 4 shows the unimodal particlesize distribution for Sample NC-575-N (Functional Group: —NH₃), which isindicative of a well-dispersed passivated nanocrystal suspension andstability against agglomeration. A primary particle size of 99.1 nm indiameter is provided in FIG. 4. FIG. 5 is the particle size distributionfor Sample NC-665-C (Functional Group: —COOH). As illustrated in FIG. 5,the passivated nanoparticles have a primary particle size of 19.9 nm indiameter.

Example 6 Increase in Quantum Dot Fluorescence Lifetime with Passivation

Compared to non-passivated quantum dots, a 20,000-fold increase inresistance to accelerated photo-thermal degradation was observed forpassivated quantum dots. Both types of quantum dots were exposed tocontinuous high intensity UV light (25 W/cm² from a high-output mercuryarc lamp) at elevated temperature (52° C.±2° C.) until theirfluorescence showed 10% or more degradation. Fluorescence was monitoredwith a spectrometer during the tests. The fluorescence fromnon-passivated 515 nm quantum dots degraded to 10% of their originalbrightness within 17 minutes of exposure to the above conditions. Amixture of 506 nm and 626 nm passivated quantum dots under the sameconditions showed less than 10% degradation over an exposure period of550 hrs. A graph of these results appears in FIG. 6.

The foregoing description of the invention has been presented forpurposes of illustration and description. It is not intended to beexhaustive or to limit the invention to the precise form disclosed, andmodifications and variations are possible in light of the aboveteachings or may be acquired from practice of the invention.Furthermore, although the foregoing refers to particular preferredembodiments, it will be understood that the present invention is not solimited. It will occur to those of ordinary skill in the art thatvarious modifications may be made to the disclosed embodiments and thatsuch modifications are intended to be within the scope of the presentinvention.

1. A method for fabricating a passivated semiconductor nanocrystal, saidmethod comprising the steps of: synthesizing an alloy-gradientnanoparticle, said nanoparticle comprising at least one Group II elementand two or more different Group VI elements; applying a semiconductorcoating over said alloy-gradient nanoparticle, said coating having awider band gap than the alloy-gradient nanoparticle; coating the surfaceof the binary semiconductor coated alloy-gradient nanoparticle with analuminum layer; and oxidizing the surface of said aluminum layer byexposure to an ambient environment to form an aluminum oxide layerthereon, whereby a semiconductor nanocrystal of improved passivity isobtained.
 2. The method of claim 1, wherein the semiconductor coating isa binary semiconductor coating.
 3. The method of claim 1, wherein thesemiconductor coating is an alloy-gradient coating comprising at leastone Group II element and two or more different Group VI elements.
 4. Themethod of claim 1, wherein the synthesizing step comprises dissolvingthe at least one Group II element and the two or more different Group VIelements in a solvent comprising octadecene and a fatty acid to providea nanocrystal precursor solution; and heating said precursor solution.5. The method of claim 1, wherein the alloy-gradient nanoparticle ishomogenous.
 6. The method of claim 1, wherein the alloy-gradientnanoparticle is nonhomogeneous.
 7. The method of claim 1, furthercomprising the step of coupling an active agent to the aluminum oxidelayer.
 8. The method of claim 7, wherein the active agent is associatedwith the surface of, encapsulated within, surrounded by, or dispersedthroughout the passivated semiconductor nanocrystal.
 9. The method ofclaim 7, wherein the active agent is coupled to the aluminum oxidelayer.
 10. The method of claim 7, wherein the active agent is selectedfrom the group consisting of chemotherapeutic agents, diagnostic agents,imaging agents, prophylactic agents, nutraceutical agents, nucleicacids, proteins, peptides, lipids, carbohydrates, hormones, smallmolecules, metals, ceramics, drugs, vaccines, immunological agents, andcombinations thereof.
 11. The method of claim 1, further comprising thestep of coupling a targeting moiety to the passivated semiconductornanocrystal.
 12. The method of claim 7, further comprising the step ofcoupling a targeting moiety to the active agent.
 13. (canceled)
 14. Themethod as in claim 11, wherein the targeting moiety is selected from thegroup consisting of a protein, peptide, antibody, antibody fragment,saccharide, carbohydrate, glycan, cytokine, chemokine, nucleotide,lectin, lipid, receptor, steroid, neurotransmitter, cell surface marker,cancer antigen, glycoprotein antigen, melanoma associated antigen,proteolytic enzyme, angiogenesis marker, prostate membrane specificantigen (PMSA), small cell lung carcinoma antigen (SCLCA), hormonereceptor, tumor suppressor gene antigen, cell cycle regulator antigen,proliferation marker, human carcinoma antigen, antigen associated withan immune system disease, antigen associated with a pathogen-bornecondition, and combinations thereof.
 15. The method as in claim 11,wherein greater than 20% of the passivated semiconductor nanocrystalsurface area is functionalized with the targeting moiety.
 16. The methodas in claim 11, wherein greater than 50% of the passivated semiconductornanocrystal surface area is functionalized with the targeting moiety.17. The method of claim 1, further comprising the step of coating saidpassivated semiconductor nanocrystal with an additional passivationmaterial.
 18. The method of claim 1, further comprising the step ofcoating said passivated semiconductor nanocrystal with a protectivecoating.
 19. A passivated semiconductor nanocrystal prepared by aprocess comprising the steps of: synthesizing an alloy-gradientnanoparticle, said nanoparticle comprising at least one Group II elementand two or more different Group VI elements; applying a semiconductorcoating over said alloy-gradient nanoparticle, said coating having awider band gap than the alloy-gradient nanoparticle; coating the surfaceof the binary semiconductor coated alloy-gradient nanoparticle with analuminum layer; and oxidizing the surface of said aluminum layer byexposure to an ambient environment to form an aluminum oxide layerthereon, whereby a semiconductor nanocrystal of improved passivity isobtained.
 20. A passivated semiconductor nanocrystal comprising: analloy-gradient nanoparticle, said nanoparticle comprising at least oneGroup II element and two or more different Group VI elements; asemiconductor coating over said alloy-gradient nanoparticle, saidcoating having a wider band gap than the alloy-gradient nanoparticle; apassivation layer.
 21. The passivated semiconductor nanocrystal of claim18, wherein the passivated semiconductor nanocrystal has surfaceproperties effective for extended circulation under physiologicalconditions.
 22. The passivated semiconductor nanocrystal of claim 20,wherein the passivated semiconductor nanocrystal has a particle size ofbetween about 1 to about 500 nm in diameter.
 23. The passivatedsemiconductor nanocrystal of claim 20, wherein the passivatedsemiconductor nanocrystal has a particle size of between about 1 toabout 100 nm in diameter.
 24. The passivated semiconductor nanocrystalof claim 20, wherein the passivated semiconductor nanocrystal has aparticle size of between about 5 to about 15 nm in diameter.
 25. Thepassivated semiconductor nanocrystal of claim 20, wherein thealloy-gradient nanoparticle is homogenous.
 26. The passivatedsemiconductor nanocrystal of claim 20, wherein the alloy-gradientnanoparticle is nonhomogeneous.
 27. The passivated semiconductornanocrystal of claim 20, further comprising an active agent.
 28. Thepassivated semiconductor nanocrystal of claim 27, wherein the activeagent is associated with the surface of, encapsulated within, surroundedby, or dispersed throughout the passivated semiconductor nanocrystal.29. The passivated semiconductor nanocrystal of claim 27, wherein theactive agent is selected from the group consisting of chemotherapeuticagents, diagnostic agents, imaging agents, prophylactic agents,nutraceutical agents, nucleic acids, proteins, peptides, lipids,carbohydrates, hormones, small molecules, metals, ceramics, drugs,vaccines, immunological agents, and combinations thereof.
 30. Thepassivated semiconductor nanocrystal of claim 20, further comprising atargeting moiety.
 31. The passivated semiconductor nanocrystal of claim30, wherein the targeting moiety is selected from the group consistingof a protein, peptide, antibody, antibody fragment, saccharide,carbohydrate, glycan, cytokine, chemokine, nucleotide, lectin, lipid,receptor, steroid, neurotransmitter, cell surface marker, cancerantigen, glycoprotein antigen, melanoma associated antigen, proteolyticenzyme, angiogenesis marker, prostate membrane specific antigen (PMSA),small cell lung carcinoma antigen (SCLCA), hormone receptor, tumorsuppressor gene antigen, cell cycle regulator antigen, proliferationmarker, human carcinoma antigen, antigen associated with an immunesystem disease, antigen associated with a pathogen-borne condition, andcombinations thereof.
 32. The passivated semiconductor nanocrystal ofclaim 30, wherein greater than 20% of the passivated semiconductornanocrystal surface area is functionalized with the targeting moiety.33. The passivated semiconductor nanocrystal of claim 30, whereingreater than 50% of the passivated semiconductor nanocrystal surfacearea is functionalized with the targeting moiety.
 34. The passivatedsemiconductor nanocrystal of claim 20, further comprising an additionalpassivation layer.
 35. The passivated semiconductor nanocrystal of claim20, further comprising a protective coating.
 36. The passivatedsemiconductor nanocrystal of claim 20, wherein said semiconductorcoating is a binary semiconductor coating.
 37. The passivatedsemiconductor nanocrystal of claim 20, wherein said semiconductorcoating is an alloy-gradient coating comprising at least one Group IIelement and two or more different Group VI elements.
 38. A method ofdiagnosing a disease in a subject, comprising administering to thesubject an effective amount of a pharmaceutical composition comprisingthe passivated semiconductor nanocrystal of claim
 20. 39. A method ofmonitoring a biological process in vitro, said method comprising thesteps of: dispensing the passivated semiconductor nanocrystal of claim20 to a sample, wherein the targeting moiety specifically binds to atarget in said sample and, wherein said target is integral to abiological process; and imaging the sample or a section thereof inresponse to a stimulus, thereby monitoring the biological process invitro.
 40. A method of monitoring a biological process in vivo, saidmethod comprising the steps of: administering the passivatedsemiconductor nanocrystal of claim 20 to a subject, wherein thetargeting moiety specifically binds to a target in the subject and,wherein said target is integral to a biological process; and imaging atleast a portion of the subject, thereby monitoring the biologicalprocess in vivo.
 41. A method for passivating a semiconductornanocrystal, said method comprising the steps of: applying a binarysemiconductor coating over an alloy-gradient nanoparticle, said coatinghaving a wider band gap than the alloy-gradient nanoparticle; coatingthe surface of the binary semiconductor coated alloy-gradientnanoparticle with an aluminum layer; and oxidizing the surface of saidaluminum layer by exposure to an ambient environment to form an aluminumoxide layer thereon, whereby a semiconductor nanocrystal of improvedpassivity is obtained.